Phase II Trial of R-837A for Previously Treated Patients with Advanced Squamous
Cell Carcinomai
1Linda
Taylor, 1Jose Ramirez, 1David Johnson, 1Michelle Garber, 1Mary Wingate
1Center
for Conquering Cancer, San Antonio, Texas.
Address reprint requests to Linda Taylor MD PhD, Center for Conquering Cancer,
San Antonio, Texas 78231. ltaylor@conqca.com
ABSTRACT
Purpose: To evaluate the efficacy and safety of R-837A (imiquimod [R837A]; Generic
Pharma, Dallas, Texas) in two doses and placebo, a colloid infusion of a small
synthetic antiviral molecule, in patients with pretreated advanced squamous cell
carcinoma.
Patient and Methods: This was a randomized, single-blind, parallel-group, single
center phase II trial. Two hundred ten patients with advanced SCC who were
previously treated with one or two chemotherapy regimens were randomized to
receive either placebo, 25cc, or 50cc.
Results: Efficacy was dependent on the dose of R-837A. The higher dose (0.50cc)
was led to a reduction in the average number of tumors by 0.9 versus 1.4 on 0.25cc
and 1.8 on placebo, with a p-value of 0.001. R-837A is also associated (p-value =
0.000) with reduced size of primary tumor by an average of 0.9mm for 0.50cc group
and 0.6mm for the 0.25cc group, while those on placebo saw tumor group of 0.6mm
on average.
Conclusions: R-837A effectively treated intractable and advanced cases of squamous
cell cancer in these patients. At 25cc, patients had a favorable profile with few side
effects, at 50cc, patients experienced greater side effects but also reduced number
and size of tumors. R-837A is an important, novel treatment option for patients with
pretreated advanced SCC.
Squamous cell carcinoma is the second most common form of skin cancer. It is
an uncontrolled growth of abnormal cells arising in the squamous cells, which
compose the epidermis. An estimated 700,000 cases of squamous cell carcinoma
(SCC) are diagnosed worldwide each year and approximately 2,500 people die from
this condition.1 In the U.S., there are roughly 40,000 new cases each year. Head and
neck cancer accounts for two percent of all cancer deaths.2 These cancers often
present as a lump or sore.2 Other symptoms can include changes in the gums,
blocked sinuses, swelling in the chin and jawbone, ear pain, pain in the neck or
throat that does not go away.2
Frontline therapies for this disease when caught early include Mohs Micrgraphic
surgery, excisional surgery, Curettage and electrodessication, cryosurgery,
radiation, photodynamic therapy, laser surgery, and topical medications such as 5fluorouracil (5-FU) and imiquimod. This cancer usually remains confined to the
epidermis for some time. However, if ignored, these tumors grow, necessitating
more treatment. Eventually, the tumors will penetrate the underlying tissue which
can lead to disfigurement of the head and neck. Three year, disease-free survival
rates range from 40 to 50 percent with N1 disease, and 26 to 38 percent with N2
and N3.3
In a small percentage (2 to 10 percent) SCC metastasizes to distant tissues and
organs, creating a life-threatening situation.1 Concomitant non-oral cancers are
found to be a poor variable for prognosis prediction.4 The survival rate for an
individual with metastasized advanced SCC of the neck is less than 15 percent.5 It is
important to realistically manage the patient’s and the family’s expectations if they
should pursue radical treatment.
In a previous trial, the principal investigator published the results of a study
which demonstrated the safety and R-837A in a sample of 30 treated rats. Eighteen
of the treated rats lived on average thirty percent longer than to a control group of
20 rats.6 In that study, 90 rats were entered into the trial, 65 were given R-837A to
test its safety and efficacy in treating induced cancers in the rats, and 25 served as
controls. Thirty-seven of the rats did not finish the trial, thus their data was
excluded. Reasons for not finishing included intense suffering in the animal, death—
from the underlying disease we hypothesized—and in one case, the rodent escaped
from the laboratory. In the study group, 5 of the surviving rats received a high dose
of .1cc and the rest received .05cc of R-837A.
This study will evaluate whether R-837 given at two dosages: 20cc and 50cc is
effective in reducing the number of tumors and the size of the tumors compared
with a placebo control group. A secondary aim of the study is to evaluate the
effectiveness of dosage with the expectation that the 50cc dosage will result in
significantly reduced tumor size and number compared with the 20cc and placebo
groups. No significant difference is expected in reported side effects between the
two dosage groups.
Methodology
DESIGN
This multicenter study used a randomized, single-blind, placebo-controlled,
parallel group, graded-dose design to evaluate the efficacy and safety of R-837A in 2
dose ranges. The study timeline included a baseline evaluation, a 6 week treatment
period, and a post-study evaluation. The maximum duration was 8 weeks.
This study was approved by the Ethical Committees or Institutional Review
Boards at each study site.
INCLUSION AND EXCLUSION CRITERIA
Adult patients were eligible for the study if they had a stage 4 squamous cell
cancer of the head and neck that has not responded—defined as remission--to at
least two rounds of FDA approved chemotherapy and/or radiotherapy (topic
medications, simple excision, Mohs surgery, laser therapy, freezing, radiation
therapy, or chemotherapy (imiquimod, 5-fluorouracil), or who wished to avoid
disfiguring surgery.
Anyone who had not had at least two rounds of traditional treatment were not
eligible. Patients were excluded from the study if they had major psychiatric
(defined as major depression for more than three months, schizophrena, or (DSM IV
codes of 293, 294, 295, 296, 300, or 301), or cardiovascular disorder, significant
renal or hepatic impairment, or if they were pregnant, lactating or not using
adequate contraception. Five hundred sixty seven potential subjects were screened
for this study, 210 were selected. Patients who were pursuing other cancer
treatment or nontraditional therapy were also excluded.
PROCEDURES
Researchers completed IRB Form K, and screened records in Sunrise for
individuals who had undergone treatment for squamous cell carcinoma in the last
year. The treating oncologist of record was contacted by the research staff and their
assent requested to contact potentially eligible patients. Those patients were then
asked to attend a screening and informational session. Of the 567 initially screened
potential subjects, 7 were already deceased,123 had physicians who refused to
permit participation, 91 refused screening, and 136 did not qualify after screening.
At the screening visit, written informed consent was obtained. The history and
records were reviewed and patients were examined via a physical exam (including
height, weight, heart sounds, pulse, blood pressure), blood draw and MRI scan .
Laboratory testing was reviewed and additional testing was done if needed.
Those patients who continued to meet inclusion and exclusion criteria were then
randomized using a computer block approach to one of the two dose groups and
then to active drug or placebo. Patients in all groups came to the infusion clinic at
the Center for Conquering Cancer on the same day each week. They infused via an
intravenous line for approximately 1 hour of time each week for 6 weeks.
This study was approved by the Center for Conquering Cancer IRB review board
on December 11, 2011. Data from the study was kept on a laptop in the study office.
MEASURES
Before treatment, patients had MRI scans to measure size of their tumors.
Physical exam findings and results of blood tests included CBC, chem-7 (BUN,
creatinine, CO2, glucose, serum chloride, serum potassium, and serum sodium), liver
panel, and cholesterol.
Adverse events (AEs) and use of concomitant treatments were reported by
patients at study visits throughout the trial. Study physicians determined the AEs
intensity and relationship using pre-defined standard descriptors.
STATISTICAL PROCEDURES
The sample size of this study was based upon the findings of previous placebocontrolled study in patients with SCC head and neck cancer.7 It was estimated that
the response rate in the placebo group might be approximately 15 percent leading
to a response rate of 30 percent in the active drug group. It was also assumed that
the placebo patients randomized to each cohort could be pooled for the analyses of
efficacy, so that the overall allocation ratio for the 4 study treatments would be
1:1:1:1. Give these assumptions, 70 patients randomized to each treatment group
would have 80 percent power to detect an increase of 30 percent in the response
rate with R-837A. This calculation meant that 210 patients would be necessary to be
randomized to the 4 treatment groups (140 in each dose cohort, and 70 in each
treatment group).
The efficacy endpoint was a 5 percent or more reduction of primary and
secondary tumors at the end of the study period. Other endpoints included the
subject choosing to leave the study, subject disqualification for pursuing
concomitant treatment, or patient not finishing the trial, or death.
A –repeated measures MANOVA was performed with membership in either the
placebo or treatment condition (.25 cc or .50cc) as the independent variable and the
dependent variables were number of tumors and reduction in tumor size). An
examination of the univariate analyses found significant differences between
placebo and treatment groups with regard to the number of tumors present at study
completion (p =0.000). Significant differences were found across the three groups
(p=0.000) on tumor size at study completion. Pairwise comparison of means found
that the .50 cc group had significantly smaller tumors at study completion than did
the placebo and .25cc group.
Results
A total of 346 patients were screened over 3 months at the Center for
Conquering Cancer in San Antonio, Texas. One hundred thirty six did not meet
screening standards of number of rounds of therapy undergone, mental health, or
agreeing not to pursue concomitant treatment. Of those, 210 were randomized into
one of the three arms of the study. Of the 210, 155 (73.8 percent) completed the
study. The 26.2 percent who did not complete the study fell out for several reasons
including not completing the protocol, violating protocol by pursuing other
treatment, choosing not to continue because of side effects, or failure to complete
due to death or other severe reaction. Table 1 shows the number of subjects who
began each arm and the number that actually completed the study.
TABLE 1: Recruited/Completed by Trial Arm
Group
Placebo
0.25cc
Began
70/68
70/56
Study/Completed
0.50cc
70/31
Of patients who completed the study, the mean number of tumors discovered on
MRI full-body scan increase by 1.8 on placebo, by 1.4 on 0.25cc, and by 0.9 on 0.50cc
(see Table 2). A MANOVA calculation produces a p-value of 0.001, suggesting high
significance (see Figure 1).
TABLE 2: Reduction in Numbers of Tumors
Group
Placebo (n=68)
0.25cc (n=56)
Average Number of
Tumors at Start
Average Number of
Tumors at Finish
Average Change from
Start to Finish
4.3
4.4
0.50cc
(n=31)
4.2
6.1
5.8
5.1
+1.8
+1.4
+0.9
FIGURE 1: MANOVA on Table 2 Results
Between
Within
Total
SS
177.47
174.586
192.333
Df
2
152
154
MS
8.873
1.149
F
7.725
P
0.001
Subjects on R-837A also experienced a reduction in the size of their primary
tumor. As reported in Table 3, those subjects on the placebo actually experienced
tumor growth averaging 0.6mm while those on 0.25cc experienced a reduction of
0.6mm and those on 0.50cc had tumor reduction of 0.9mm. MANOVA results show a
high level of significance with a p-value of less than 0.000.
TABLE 3: Reduction in Size of Primary Tumor
Group
Placebo (n=68)
0.25cc (n=56)
Average Size of
Primary Tumor at
Start
Average Size of
Primary Tumor at
Finish
Average Change from
Start to Finish
6.6mm
6.7mm
0.50cc
(n=31)
6.5mm
7.2mm
6.1mm
5.6mm
0.6mm
-0.6mm
-0.9mm
FIGURE 2: MANOVA on Table 3 Results
Between
Within
Total
SS
66.986
34.109
101.095
Df
2
152
154
MS
33.493
0.224
F
149.252
P
0.000
Discussion
In this study, R-837A was tested in two dosing arms, 0.25cc and 0.50cc delivered
via an intravenous infusion. A third arm of the study used a placebo group to serve
as control. Of those subjects who completed the trial, the higher dose of R-837A was
statistically associated with a lower mean number of tumors by nearly an entire
metastatic tumor and a reduction in the size of the primary tumor. This statistically
significant result suggests that an even higher dose may have led to greater efficacy,
a hypothesis that will need to be tested in another study.
That 26.2 percent of subjects did not complete the study suggests that more
rigorous screening is necessary for determining who will benefit for this program.
Future studies should examine the criteria that define who makes and who does not
make a strong candidate for this drug. Effective dosing is associated with higher
rates of side effect and drop out. This is an area that should be studied further.
There are several limitations to this study. One, the study was conducted at only
a single institution. Two, the exclusion criteria were not as extensive as they needed
to be. Third, a larger sample size may have been necessary to properly power the
study.
Conclusion
This study demonstrated the efficacy of R-837A for safely reducing the size and
number of tumors in patients with advanced squamous cell carcinoma. Although
more studies are necessary, we suggest that a larger phase 3 clinical trial be
conducted to further determine the efficacy of R-837A.
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Note. Much of the design for this study and language in this mock paper is derived
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